tbuckley/cabot-search huggingface dataset:
Phase II Investigation of TVB-2640 (Denifanstat) with Bevacizumab in Patients with First Relapse High-Grade Astrocytoma
Authors: William Kelly, Adolfo Enrique Diaz Duque, Joel Michalek, Brandon Konkel, Laura Caflisch, Yidong Chen, Sarath Chand Pathuri, Vinu Madhusudanannair-Kunnuparampil, John Floyd, Andrew Brenner
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Glioblastoma represents the most common primary brain tumor. Although antiangiogenics are used in the recurrent setting, they do not prolong survival. Glioblastoma is known to upregulate fatty acid synthase (FASN) to facilitate lipid biosynthesis. TVB-2640, a FASN inhibitor, impairs this activity. Patients and Methods: We conducted a prospective, single-center, open-label, unblinded, phase II study of TVB-2640 plus bevacizumab in patients with recurrent high-grade astrocytoma. Patients were randomly assigned to TVB-2640 (100 mg/m2 oral daily) plus bevacizumab (10 mg/kg i.v., D1 and D15) or bevacizumab monotherapy for cycle 1 only (28 days) for biomarker analysis. Thereafter, all patients received TVB-2640 plus bevacizumab until treatment-related toxicity or progressive disease (PD). The primary endpoint was progression-free survival (PFS). Results: A total of 25 patients were enrolled. The most frequently reported adverse events (AE) were palmar–plantar erythrodysesthesia, hypertension, mucositis, dry eye, fatigue, and skin infection. Most were grade 1 or 2 in intensity. The overall response rate (ORR) for TVB-2640 plus bevacizumab was 56% (complete response, 17%; partial response, 39%). PFS6 for TVB-2640 plus bevacizumab was 31.4%. This represented a statistically significant improvement in PFS6 over historical bevacizumab monotherapy (BELOB 16%; P = 0.008) and met the primary study endpoint. The observed OS6 was 68%, with survival not reaching significance by log-rank test (P = 0.56). Conclusions: In this phase II study of relapsed high-grade astrocytoma, TVB-2640 was found to be a well-tolerated oral drug that could be safely combined with bevacizumab. The favorable safety profile and response signals support the initiation of a larger multicenter trial of TVB-2640 plus bevacizumab in astrocytoma.
Management of chronic myeloid leukemia in 2023 – common ground and common sense
Authors: Jayastu Senapati, Koji Sasaki, Ghayas C. Issa, Jeffrey H. Lipton, Jerald P. Radich, Elias Jabbour, Hagop M. Kantarjian
Journal: Blood Cancer Journal (2023)

Abstract With the improving knowledge of CML and its management, the goals of therapy need to be revisited to ensure an optimal use of the BCR::ABL1 TKIs in the frontline and later-line therapy of CML. In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results. The second-generation TKIs may produce earlier deep molecular responses, hence reducing the time to reaching a treatment-free remission (TFR). The choice of the second-generation TKI versus imatinib in frontline therapy is based on the treatment aims (survival, TFR), the CML risk, the drug cost, and the toxicity profile with respect to the patient’s comorbidities. The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI. In patients who are not candidates for TFR, BCR::ABL1 (International Scale) transcripts levels &lt;1% are acceptable, result in virtually similar survival as with deeper molecular remissions, and need not warrant a change of TKI. For patients with true resistance to second-generation TKIs or with the T315I gatekeeper mutation, the third-generation TKIs are preferred. Ponatinib should be considered first because of the cumulative experience and results in the CML subsets, including in T315I-mutated CML. A response-based dosing of ponatinib is safe and leads to high TKI compliance. Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results.
Tackling Osimertinib Resistance in EGFR-Mutant Non–Small Cell Lung Cancer
Authors: Juan Bautista Blaquier, Sandra Ortiz-Cuaran, Biagio Ricciuti, Laura Mezquita, Andrés Felipe Cardona, Gonzalo Recondo
Journal: Clinical Cancer Research (2023)

The current landscape of targeted therapies directed against oncogenic driver alterations in non-small cell lung cancer (NSCLC) is expanding. Patients with EGFR-mutant NSCLC can derive significant benefit from EGFR tyrosine kinase inhibitor (TKI) therapy, including the third-generation EGFR TKI osimertinib. However, invariably, all patients will experience disease progression with this therapy mainly due to the adaptation of cancer cells through primary or secondary molecular mechanisms of resistance. The comprehension and access to tissue and cell-free DNA next-generation sequencing have fueled the development of innovative therapeutic strategies to prevent and overcome resistance to osimertinib in the clinical setting. Herein, we review the biological and clinical implications of molecular mechanisms of osimertinib resistance and the ongoing development of therapeutic strategies to overcome or prevent resistance.
Preterm Birth, Small for Gestational Age, and Large for Gestational Age and the Risk of Atrial Fibrillation Up to Middle Age
Authors: Fen Yang, Imre Janszky, Mika Gissler, Sven Cnattingius, Nathalie Roos, Maohua Miao, Wei Yuan, Jiong Li, Krisztina D. László
Journal: JAMA Pediatrics (2023)

Adverse birth outcomes, including preterm birth, small for gestational age (SGA), and large for gestational age (LGA) are associated with increased risks of hypertension, ischemic heart disease, stroke, and heart failure, but knowledge regarding their associations with atrial fibrillation (AF) is limited and inconsistent.To investigate whether preterm birth, SGA, or LGA are associated with increased risks of AF later in life.This multinational cohort study included Danish, Swedish, and Finnish national health registries. Live singleton births in Denmark from 1978 through 2016, in Sweden from 1973 through 2014, and in Finland from 1987 through 2014, who were followed up until December 31, 2016, in Denmark, December 31, 2021, in Sweden, and December 31, 2014, in Finland were included. Data analyses were performed between January 2021 and August 2022.Preterm birth (less than 37 gestational weeks), SGA (less than 10th percentile birth weight for gestational age), and LGA (more than 90th percentile birth weight for gestational age) identified from medical birth registers.Diagnosis of AF obtained from nationwide inpatient and outpatient registers. The study team ran multivariable Cox proportional hazard models and flexible parametric survival models to estimate hazard ratios (HRs) and 95% CIs for AF according to preterm birth, SGA, and LGA. Sibling analyses were conducted to control for unmeasured familial factors.The cohort included 8 012 433 study participants (maximum age, 49 years; median age, 21 years; male, 51.3%). In 174.4 million person-years of follow-up, 11 464 participants had a diagnosis of AF (0.14%; median age, 29.3 years). Preterm birth and LGA were associated with increased AF risk in both the full population cohort and in the sibling analyses; the multivariate HRs from the cohort analyses were 1.30 (95% CI, 1.18-1.42) and 1.55 (95% CI, 1.46-1.63), respectively. Preterm birth was more strongly associated with AF in childhood than in adulthood. Children born SGA had an increased risk of AF in the first 18 years of life but not afterwards.Preterm births and LGA births were associated with increased risks of AF up to middle age independently of familial confounding factors. Individuals born SGA had an increased AF risk only during childhood.
Reciprocal Changes and Emergent Trips to the Catheterization Laboratory
Authors: Michael Brouner, Jamey Hammock, Harish Doppalapudi
Journal: JAMA Internal Medicine (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction
Authors: Michael Böhm, Amr Abdin, Jonathan Slawik, Felix Mahfoud, Jeffrey Borer, Ian Ford, Karl Swedberg, Luigi Tavazzi, Cécile Batailler, Michel Komajda
Journal: European Journal of Heart Failure (2023)

Aims In the SHIFT (Systolic Heart failure treatment with the I f inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF. Methods and results The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all‐cause death, and HF death, were assessed in a post‐hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all‐cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all‐cause death after 169 days. Conclusion Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline‐directed medication, including beta‐blockers at maximally tolerated doses.
Gut microbiome at the crossroad of genetic variants and behavior disorders
Authors: Lingsha Cheng, Haoqian Wu, Zhuo Chen, Haiping Hao, Xiao Zheng
Journal: Gut Microbes (2023)

Genetic variants are traditionally known to shape the susceptibility to neuropsychiatric disorders. An increasing number of studies indicate that remodeling of the gut microbiome by genetic variance serves as a versatile regulator of gut-brain crosstalk and behavior. Evidence also emerges that certain behavioral symptoms are specifically attributed to gut microbial remodeling and gut-to-brain signals, which necessitates rethinking of neuropsychiatric disease etiology and treatment from a systems perspective of reciprocal gene-microbe interactions. Here, we present an emerging picture of how gut microbes and host genetics interactively shape complex psychiatric phenotypes. We illustrate the growing understanding of how the gut microbiome is shaped by genetic changes and its connection to behavioral outcome. We also discuss working strategies and open questions in translating associative gene-microbiome-behavior findings into causal links and novel targets for neurobehavioral disorders. Dual targeting of the genetic and microbial factors may expand the space of drug discovery for neuropsychiatric diseases.
Thromboembolic events in peripartum cardiomyopathy: Results from the <scp>ESC EORP PPCM</scp> registry
Authors: Jasper Tromp, Alice M. Jackson, Magdy Abdelhamid, Doaa Fouad, Ghada Youssef, Mark C. Petrie, Johann Bauersachs, Karen Sliwa, Peter van der Meer
Journal: European Journal of Heart Failure (2023)
A distinct microbiota signature precedes the clinical diagnosis of hepatocellular carcinoma
Authors: Jinhuan Yang, Qikuan He, Fei Lu, Kaiwen Chen, ZhiHao Ni, Haoyue Wang, Chen Zhou, Yaosheng Zhang, Bo Chen, Zhiyuan Bo, Jialiang Li, Haitao Yu, Yi Wang, Gang Chen
Journal: Gut Microbes (2023)

Oral, gut, and tumor microbiota have been implicated as important regulators in the carcinogenesis and progression of gastrointestinal malignancies. However, few studies focused on the existence and association of resident microbes within different body regions. Herein, we aim to reveal the durability of the oral-gut-tumor microbiome and its diagnostic performance in hepatocellular carcinoma (HCC). Our study included two cohorts: a retrospective discovery cohort of 364 HBV-HCC patients and 160 controls with oral or fecal samples, a prospective validation cohort of 91 cases, and 124 controls for matching samples, as well as 48 HBV, and 39 HBV-cirrhosis patients for gut microbial patterns examined by 16S rRNA gene sequencing. With the random forest analysis, 10 oral and 9 gut genera that could distinguish HCC from controls in the retrospective cohort were validated among the prospective matching participants, with area under the curve (AUC) values of 0.7971 and 0.8084, respectively. When influential taxa were merged, the AUC of the consistent classifier increased to 0.9405. The performance continued to improve to 0.9811 when combined with serum levels of alpha-fetoprotein (AFP). Specifically, microbial biomarkers represented by Streptococcus displayed a constantly increasing trend during the disease transition. Furthermore, the presence of several dominant microbiota species was confirmed in hepatic tumor and non-tumor tissues with fluorescence in situ hybridization (FISH) and 5 R 16S rRNA gene sequencing. Overall, our findings based on the oral-gut-tumor microbiota provide a reliable approach for the early detection of HCC.
An Unusual Tracing
Authors: Sameer Kassem, Jochanan E. Naschitz
Journal: JAMA Internal Medicine (2023)

This case report presents the electrocardiogram findings of a patient in their 90s with end-stage dementia, pressure ulcers, extrapyramidal syndrome, paroxysmal atrial fibrillation, and hypothyroidism who experienced a massive aspiration of gastric content.
NGS-defined measurable residual disease (MRD) after initial chemotherapy as a prognostic biomarker for acute myeloid leukemia
Authors: Yonghong Li, Jose Solis-Ruiz, Fei Yang, Nicola Long, Carmen H. Tong, Felicitas L. Lacbawan, Frederick K. Racke, Richard D. Press
Journal: Blood Cancer Journal (2023)

Abstract Treated AML patients often have measurable residual disease (MRD) due to persisting low-level clones. This study assessed whether residual post-treatment somatic mutations, detected by NGS, were significantly prognostic for subsequent clinical outcomes. AML patients ( n = 128) underwent both pre-and post-treatment testing with the same 42-gene MRD-validated NGS assay. After induction, 59 (46%) patients were mutation-negative (0.0024 VAF detection limit) and 69 (54%) had ≥1 persisting NGS-detectable mutation. Compared with NGS-negative patients, NGS-positive patients had shorter overall survival (17 months versus median not reached; P = 0.004; hazard ratio = 2.2 [95% CI: 1.3–3.7]) and a shorter time to relapse (14 months versus median not reached; P = 0.014; HR = 1.9 [95% CI: 1.1–3.1]). Among 95 patients with a complete morphologic remission (CR), 43 (45%) were MRD-positive by NGS and 52 (55%) were MRD-negative. These MRD-positive CR patients had a shorter overall survival (16.8 months versus median not reached; P = 0.013; HR = 2.1 [95% CI: 1.2–3.9]) than did the MRD-negative CR patients. Post-treatment persisting MRD positivity, defined by the same NGS-based test used at diagnosis, is thus a more sensitive biomarker for low-level leukemic clones compared to traditional non-molecular methods and is prognostic of subsequent relapse and death.
Suicide in young people: screening, risk assessment, and intervention
Authors: Jennifer L Hughes, Lisa M Horowitz, John P Ackerman, Molly C Adrian, John V Campo, Jeffrey A Bridge
Journal: BMJ (2023)

Abstract Suicide is the fourth leading cause of death among young people worldwide and the third leading cause of death among those in the US. This review outlines the epidemiology of suicide and suicidal behavior in young people. It discusses intersectionality as an emerging framework to guide research on prevention of suicide in young people and highlights several clinical and community settings that are prime targets for implementation of effective treatment programs and interventions aimed at rapidly reducing the suicide rate in young people. It provides an overview of current approaches to screening and assessment of suicide risk in young people and the commonly used screening tools and assessment measures. It discusses universal, selective, and indicated evidence based suicide focused interventions and highlights components of psychosocial interventions with the strongest evidence for reducing risk. Finally, the review discusses suicide prevention strategies in community settings and considers future research directions and questions challenging the field.
Cooperative phagocytosis of solid tumours by macrophages triggers durable anti-tumour responses
Authors: Lawrence J. Dooling, Jason C. Andrechak, Brandon H. Hayes, Siddhant Kadu, William Zhang, Ruby Pan, Manasvita Vashisth, Jerome Irianto, Cory M. Alvey, Leyuan Ma, Dennis E. Discher
Journal: Nature Biomedical Engineering (2023)
Single-cell transcriptomic landscape of the developing human spinal cord
Authors: Jimena Andersen, Nicholas Thom, Jennifer L. Shadrach, Xiaoyu Chen, Massimo Mario Onesto, Neal D. Amin, Se-Jin Yoon, Li Li, William J. Greenleaf, Fabian Müller, Anca M. Pașca, Julia A. Kaltschmidt, Sergiu P. Pașca
Journal: Nature Neuroscience (2023)
A shared neural basis underlying psychiatric comorbidity
Authors: Chao Xie, Shitong Xiang, Chun Shen, Xuerui Peng, Jujiao Kang, Yuzhu Li, Wei Cheng, Shiqi He, Marina Bobou, M. John Broulidakis, Betteke Maria van Noort, Zuo Zhang, Lauren Robinson, Nilakshi Vaidya, Jeanne Winterer, Yuning Zhang, Sinead King, Tobias Banaschewski, Gareth J. Barker, Arun L. W. Bokde, Uli Bromberg, Christian Büchel, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Hervé Lemaître, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Juliane H. Fröhner, Ulrike Schmidt, Julia Sinclair, Michael N. Smolka, Argyris Stringaris, Henrik Walter, Robert Whelan, Sylvane Desrivières, Barbara J. Sahakian, Trevor W. Robbins, Gunter Schumann, Tianye Jia, Jianfeng Feng, Betteke Maria van Noort
Journal: Nature Medicine (2023)

Abstract Recent studies proposed a general psychopathology factor underlying common comorbidities among psychiatric disorders. However, its neurobiological mechanisms and generalizability remain elusive. In this study, we used a large longitudinal neuroimaging cohort from adolescence to young adulthood (IMAGEN) to define a neuropsychopathological (NP) factor across externalizing and internalizing symptoms using multitask connectomes. We demonstrate that this NP factor might represent a unified, genetically determined, delayed development of the prefrontal cortex that further leads to poor executive function. We also show this NP factor to be reproducible in multiple developmental periods, from preadolescence to early adulthood, and generalizable to the resting-state connectome and clinical samples (the ADHD-200 Sample and the STRATIFY &amp; ESTRA Project). In conclusion, we identify a reproducible and general neural basis underlying symptoms of multiple mental health disorders, bridging multidimensional evidence from behavioral, neuroimaging and genetic substrates. These findings may help to develop new therapeutic interventions for psychiatric comorbidities.
Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial
Authors: Catherine J. Mummery, Anne Börjesson-Hanson, Daniel J. Blackburn, Everard G. B. Vijverberg, Peter Paul De Deyn, Simon Ducharme, Michael Jonsson, Anja Schneider, Juha O. Rinne, Albert C. Ludolph, Ralf Bodenschatz, Holly Kordasiewicz, Eric E. Swayze, Bethany Fitzsimmons, Laurence Mignon, Katrina M. Moore, Chris Yun, Tiffany Baumann, Dan Li, Daniel A. Norris, Rebecca Crean, Danielle L. Graham, Ellen Huang, Elena Ratti, C. Frank Bennett, Candice Junge, Roger M. Lane
Journal: Nature Medicine (2023)

Tau plays a key role in Alzheimer's disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPT
Neural dynamics and architecture of the heading direction circuit in zebrafish
Authors: Luigi Petrucco, Hagar Lavian, You Kure Wu, Fabian Svara, Vilim Štih, Ruben Portugues
Journal: Nature Neuroscience (2023)

Abstract Animals generate neural representations of their heading direction. Notably, in insects, heading direction is topographically represented by the activity of neurons in the central complex. Although head direction cells have been found in vertebrates, the connectivity that endows them with their properties is unknown. Using volumetric lightsheet imaging, we find a topographical representation of heading direction in a neuronal network in the zebrafish anterior hindbrain, where a sinusoidal bump of activity rotates following directional swims of the fish and is otherwise stable over many seconds. Electron microscopy reconstructions show that, although the cell bodies are located in a dorsal region, these neurons arborize in the interpeduncular nucleus, where reciprocal inhibitory connectivity stabilizes the ring attractor network that encodes heading. These neurons resemble those found in the fly central complex, showing that similar circuit architecture principles may underlie the representation of heading direction across the animal kingdom and paving the way to an unprecedented mechanistic understanding of these networks in vertebrates.